N-alkenyl-2-hydroxybenzo(b)thiophene-3-carboxamide derivatives as dual cyclooxygenase and lipoxygenase inhibitors

ABSTRACT

N-Alkenyl-2-hydroxybenzo[b]thiophene-3-carboxamide derivatives are prepared via treatment of the corresponding unsubstituted carboxamide with appropriate agents, such as aldehydes, ketones, enol ethers, epoxides, acetals or ketals. 
     These compounds have been found to be effective inhibitors of both cyclooxygenase and lipoxygenase and thereby useful in the treatment of pain, fever, inflammation, arthritic conditions, asthma, allergic disorders, skin diseases, cardiovascular disorders, psoriasis, inflammatory bowel disease, glaucoma or other prostaglandins and/or leukotriene mediated diseases.

BACKGROUND OF THE INVENTION

This invention relates to benzothiophenes, particularly2-hydroxybenzothiophenes having the unusual 3-enamido side chains, forexample, ##STR1##

These novel compounds can be effective cyclooxygenase and 5-lipoxygenaseinhibitors and therefore can be useful in the treatment of inflammationand other prostaglandins and/or leukotriene mediated diseases.

Among various potent biological mediators derived from the oxygenationof arachidonic acid, prostaglandins and leukotrienes have been linked tovarious diseases. Notably, the biosynthesis of prostaglandins has beenidentified as a cause of inflammation, arthritic conditions (e.g.,rheumatoid arthritis, osteoarthritis and gout), psoriasis, inflammatorybowel disease, and pain. Furthermore, the formation of leukotrienes hasbeen connected to immediate hypersensitivity reactions andproinflammatory effects. It has been established that arachidonic acidundergoes oxygenation via two major enzymatic pathways:

(1) The pathway catalyzed by the enzyme cyclooxygenase; and

(2) The pathway catalyzed by the enzyme 5-lipoxygenase.

Interruption of these pathways by enzyme inhibition has been exploredfor effective therapy. For example, non-steroidal anti-inflammatorydrugs (NSAID) such as aspirin, indomethacin and diflunisal are knowncyclooxygenase inhibitors which inhibit the process wherein arachidonicacid is oxygenated via cyclooxygenase to prostaglandins andthromboxanes.

Recently, it has been observed that certain leukotrienes are responsiblefor diseases related to immediate hypersensitivity reactions such ashuman asthma, allergic disorders, and skin diseases. In addition,certain leukotrienes and derivatives thereof are believed to play animportant role in causing inflammation (B. Samuelsson, Science, 220, 568(1983); D. Bailey et al. Ann. Rpts. Med. Chem., 17, 203 (1982)).

Through recent research, 5-lipoxygenase inhibitors has been linked tothe treatment of eye inflammation and used as cytoprotective agents.

To be an effective and acceptable topical agent for treating eyeinflammation, a drug must not only penetrate the ophthalmic tissues toreach the active sites within the eye, but it must also be devoid ofthose side effects including irritation, allergic reaction and the likewhich would militate against long term administration.

With respect to the cytoprotective activity, it has been known that (1)gastric cytoprotection does not involve inhibition of gastric acidsecretion. For example, protaglandin F2B does not inhibit gastric acidsecretion, but it does induce gastric cytoprotection (S. Szabo et al.,Experimentia, 38, 254, 1982); (2) lower effective dosages ofcytoprotective agents are required than that of gastric acid inhibitors;and (3) the cytoprotective activity of a compound may be observed inboth animals and man by noting the increased resistance ofgastrointestinal mucosa to strong irritants. For example, animal studieshave shown that cytoprotective compounds will prevent gastric lesionsinduced by oral administration of strong acids, strong bases, ethanol,hypertonic saline, etc.

DETAILED DESCRIPTION OF THE INVENTION

A. Scope of the Invention

The present invention relates to novel compounds of formula (I):##STR2## or a pharmaceutically acceptable salt thereof wherein R is

(a) H;

(b) loweralkyl, especially C₁₋₆ alkyl such as methyl, ethyl, i-propyl,n-propyl, t-butyl, n-butyl, i-pentyl, n-pentyl and n-hexyl;

(c) aryl especially C₆₋₁₄ aryl e.g., naphthyl, anthryl, phenyl orsubstituted phenyl of formula ##STR3## wherein X₅ and X₆ independentlyare: (1) Q, where Q is H, loweralkyl especially C₁₋₆ alkyl,haloloweralkyl especially fluoro or chloro C₁₋₆ alkyl such astrifluoromethyl, phenyl or substituted phenyl, or naphthyl;

(2) halo especially chloro, fluoro, bromo or iodo;

(3) loweralkenyl especially C₂₋₆ alkenyl such as ethenyl and allyl;

(4) loweralkynyl especially C₂₋₆ alkynyl, for example, ethynyl orn-butynyl;

(5) --SQ;

(6) --OQ;

(7) --CHQCOQ¹, where Q is Q¹ and can be the same as or different from Q¹;

(8) --CHQCOOQ¹ ;

(10) --CH₂ SQ or --CHQSQ¹ ;

(11) --CH₂ OQ or --CHQOQ¹ ;

(12) --COQ;

(13) --COOQ;

(14) --OCOQ;

(15) --NQQ¹ ;

(16) --NQCOQ¹ ;

(17) --NQ(OQ¹);

(18) --NQ(SQ¹);

(19) --NQSO₂ Q¹ ;

(20) --SO₂ NQQ¹ ;

(21) --SOQ;

(22) --SO₂ Q;

(23) --SO₃ Q;

(24) --CN;

(25) --NO₂ ;

(26) --CONQQ¹ ;

(27) --NO;

(28) --CSQ;

(29) --CSNQQ¹ ;

(30) --CF₂ SQ;

(31) --CF₂ OQ;

(32) --NQCONHQ¹ or NQCONQ¹ Q² wherein Q² is Q¹ and can be the same as ordifferent from either Q or Q¹ ;

(d) lowercycloalkyl especially C₃₋₆ cycloalkyl, e.g., cyclopropyl,cyclopentyl and cyclohexyl;

(e) haloloweralkyl especially halo C₁₋₆ alkyl, e.g. CF₃ --, CHF₂ --, C₂F₅ --;

(f) heteroaryl or heteroaryl substituted with X₅ and X₆ especiallypyridyl, pyrryl, furyl or thienyl wherein X₅ and X₆ are as previouslydefined;

(g) benzyl or substituted benzyl of formula ##STR4## wherein X₅ and X₆are as previously defined; (h) loweralkynyl especially C₁₋₆ alkynyl suchas --C.tbd.CH; CH₃ --C.tbd.C--, or HC.tbd.C--CH₂ --;

(i) loweralkenyl especially C₁₋₆ alkenyl, such as CH₂ ═CH--, CH₃CH═CH--, CH₂ ═CHCH₂ --, CH₃ CH═CH--CH₂ -- or (CH₃)₂ C═CH;

(j) phenylloweralkenyl of formula ##STR5## where X₅ and X₆ are aspreviously defined; or (k) phenylloweralkynyl of formula ##STR6## whereX₅ and X₆ are as previously defined; ##STR7## wherein R⁵ is R; ##STR8##wherein R⁶ is R⁵ and can be the same as or different from R⁵ ; ##STR9##wherein m is 1 or 2; ##STR10## n is 0, 1 or 2; X₁, X₂, X₃ and X₄independently are

(a) R as previously defined; or

(b) X₅ ;

R¹, R² and R³ independently are

(a) R; or

(b) R² and R³ joined together forming a ring of structure ##STR11##wherein X₅ and X₆ are as previously defined and Y is (CH₂)_(n), O, S,SO, SO₂, NQ; or

(c) halo;

R⁴ is

(a) R; or

(b) --CR¹ ═CR² R³ ;

Preferably, a dual enzyme inhibitor of this invention is of formula:##STR12## wherein X₂, X₃, R, R¹, R², R³, R⁴ and n are as previouslydefined.

More preferably, a dual enzyme inhibitor of this invention is offormula: ##STR13## wherein X₂, X₃, R, R¹, R², R³ and R⁴ are aspreviously defined.

Even more preferably, a dual enzyme inhibitor of this invention is offormula: ##STR14## wherein X₂ is

(a) H;

(b) loweralkyl;

(c) haloloweralkyl especially halo-C₁₋₆ alkyl such as CF₃ ;

(d) loweralkenyl especially C₂₋₆ alkenyl; or

(e) halo;

R is H or C₁₋₆ alkanoyl;

R² and R³ independently are:

(a) loweralkyl;

(b) phenyl or substituted phenyl;

(c) heteroaryl or substituted heteroaryl especially thienyl, furyl orpyrryl; and

R⁴ is H or --CH═CHR².

The following are some representative compounds of the presentinvention:

N-(2,2-diphenylethenyl)-2-hydroxybenzo[b]thiophene-3-carboxamide;

N-(2,2-diphenylethenyl)-2-hydroxy-5-(trifluoromethyl)benzo[b]thiophene-3-carboxamide;

N-(2,2-diphenylethenyl)-2-hydroxy-6-(trifluoromethyl)benzo[b]thiophene-3-carboxamide;

N-(2,2-di-2-thienyl)-2-hydroxybenzo[b]thiophene-3-carboxamide;

N-[2-phenyl-2-(2-thienyl)ethenyl]-2-hydroxybenzo[b]thiophene-3-carboxamide;

N-[2-(2-furyl)-2-phenylethenyl]-2-hydroxybenzo[b]thiophene-3-carboxamide;

N-methyl-N-(2,2-diphenylethenyl)-2-hydroxybenzo[b]thiophene-3-carboxamide;

N-(2,2-diphenylethenyl)-5-fluoro-2-hydroxybenzo[b]thiophene-3-carboxamide;

N-[2-phenyl-2-(2-thienyl)-ethenyl]-5-cyano-2-hydroxybenzo[b]thiophene-3-carboxamide;

N-[2-phenyl-2-(2-thienyl)-ethenyl]-5-fluoro-2-hydroxy-6-methoxybenzo[b]thiophene-3-carboxamide;

N-[2-phenyl-2-(p-methylthiophenyl)-ethenyl]-2-hydroxy-5-(trifluoromethyl)-benzo[b]thiophene-3-carboxamide;

N-[2-(p-methylthiophenyl)-2-(2-thienyl)-ethenyl]-2-hydroxybenzo[b]thiophene-3-carboxamide;

N-(2,2-diphenylethenyl)-5-(difluoromethyl)-2-hydroxybenzo[b]thiophene-3-carboxamide;

N-[2-phenyl-2-(2-thienyl)-ethenyl]-5-(1,1-difluoroethyl)-2-hydroxybenzo[b]thiophene-3-carboxamide;

N-[2-(3-methyl-2-furyl)-2-phenylethenyl]-5-chloro-2-hydroxybenzo[b]thiophene-3-carboxamide;

N-(2,2-diphenylethenyl)-5-formyl-2-hydroxybenzo[b]thiophene-3-carboxamide;

N-[2-(m-fluorophenyl)-2-phenylethenyl]-2-hydroxy-5-(methylthio)-benzo[b]thiophene-3-carboxamide;

N-[2-(o-fluorophenyl)-2-phenylethenyl]-2-hydroxy-5-(methylthio)-benzo[b]thiophen-3-carboxamide;

N-[2-phenyl-2-(2-thienyl)ethenyl]-2-hydroxy-5-(methylsulfinyl)-benzo[b]thiophene-3-carboxamide.

B. Preparation of the Compounds of the Invention

The compounds of the present invention are prepared from known startingmaterials via the following method:

N-alkenylation:

An appropriately substituted 2-hydroxybenzo[b]thiophene-3-carboxamide isreacted with an N-alkenylation reagent containing a carbonyl group orthe equivalent thereof according to the following scheme: ##STR15##wherein the acid is a strong organic or inorganic acid or a mixturethereof, for example, arylsulfonic acid such as p-toluenesulfonic acidmonohydrate, H₂ SO₄, HCl, H₃ PO₄, trifluoroacetic acid, alkylsulfonicacid such as methylsulfonic acid, acetic acid, trichloroacetic acid orthe like.

The requisite amides, namely substituted2-hydroxybenzo[b]thiophene-3-carboxamides (I) are prepared via a varietyof procedures known to those well versed in the art (See scheme). Thefollowing examples are representative but not limiting: ##STR16## E.g.,the known 2-oxobenzothiophene (II) may be converted to 3-carboxamide viaseveral routes, including the reaction with phenyl carbamates (G.B. No.2,024,220); the conversion of benzothiophen-2,3-dione (III; J. Org.Chem., 727 (1949)) via standard means to the corresponding 3-aldehydeand carboxylic acid, and thence to the amide (A); the conversion ofBenzothiophene-3-carboxamides (IV) via oxidation, or other indirectroutes to (A); the cyclization of the α-(o-mercaptophenyl)malonamicacids derivatives (V) (G.B. No. 2,024,220) to the correspondingbenzothiophene-3-carboxamides; or the transformation of2-aminobenzthiophenes (VI, Berichte, 101 (1968), 1936) appropriatelysubstituted at the 3-position to the 2-hydroxy compound (A) viadiazotization or direct hydrolysis (J. Org. Chem., 30, 4078 (1965)).

Condensation of (A) with the various N-alkylation agents, e.g., those offormula (B) may then be accomplished via procedures previously disclosedin the copending application Ser. No. 705,115 filed Feb. 27, 1985:##STR17##

The pharmaceutically acceptable salts of compounds of Formula I (at the2-hydroxy site when R is H) are readily prepared by conventionalprocedures well-known in the art. For example, a compound of Formula Iis treated with an appropriate amount of a base, such as an alkali oralkaline earth metal hydroxide, e.g. sodium hydroxide, potassiumhydroxide, and calcium hydroxide or an organic base such as an alkoxide,e.g., CH₃ ONa, t-BuOk, or the like.

The pharmaceutically acceptable esters of the phenol of formula (I) canalso be prepared by conventional methods. For example, (1) a compound ofFormula (I) is treated with an acyl halide such as acetylchloride or anacid anhydride such as acetic acid anhydride.

C. Utility of the compounds within the scope of the invention

This invention also relates to a method of treatment for patients (ormammalian animals raised in the dairy, meat, or fur industries or aspets) suffering from disorders or diseases mediated by prostaglandinsand/or leukotrienes, and gastric irritation or lesion. Morespecifically, this invention is directed to a method of treatmentinvolving the administration of one or more of the dual enzymeinhibitors of formula (I) as the active constituent.

Accordingly, a compound of Formula (I) can be used among other things toreduce pain and inflammation, to correct respiratory, cardiovascular,and intravascular alterations or disorders, and to regulate immediatehypersensitivity reactions that cause human asthma and allergicconditions.

For the treatment of inflammation, arthritis conditions, cardiovasculardisorder, allergy, psoriasis, asthma, or other diseases mediated byprostaglandins and/or leukotrienes, a compound of Formula (I) may beadministered orally, topically, parenterally, by inhalation spray orrectally in dosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intravascular injection or infusion techniques. Inaddition to the treatment of warm-blooded animals such as mice, rats,horses, cattle, sheep, dogs, cats, etc., the compounds of the inventionare effective in the treatment of humans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or algenic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid. Dispersible powders and granulessuitable for preparation of an aqueous suspension by the addition ofwater provide the active ingredient in admixture with a dispersing orwetting agent, suspending agent and one or more preservatives. Suitabledispersing or wetting agents and suspending agents are exemplified bythose already mentioned above. Additional excipients, for examplesweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of Formula (I) may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds of Formula (I) are employed.

Dosage levels of the order of from about 0.01 mg to about 150 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7.5 gms. per patientper day). For example, inflammation may be effectively treated by theadministration of from about 0.2 to 50 mg of the compound per kilogramof body weight per day (about 20 mg to about 3.5 gms per patient perday). Preferably a dosage of from about 1 mg to about 20 mg per kilogramof body weight per day may produce good results (about 25 mg to about 1gm per patient per day).

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 0.5 mg to 5 gm of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain between from about 1 mg to about 500 mg of an activeingredient.

Particularly, for use in treatment of ophthalmic conditions includingthose associated with elevated intraocular pressure such as glaucoma orother inflammation in the eye. The active compound can be administeredtopically or systemically when it is appropriate. The dose administeredcan be from a little as 0.1 to 25 mg or more per day, singly, orpreferably on a 2 to 4 dose per day regimen although a single dose perday is satisfactory.

When given systemically, the drug can be given by any route, althoughthe oral route is preferred. In oral administration the drug can beemployed in any of the usual dosage forms such as tablets or capsules,either in a contemporaneous delivery or sustained release form. Anynumber of the usual excipients or tableting aids can likewise beincluded.

When given by the topical route, the active drug or anophthalmologically acceptable salt thereof such as the sodium orpotassium salt is formulated into an ophthalmic preparation. In suchformulations, from 0.1% to 15% by weight can be employed. The objectiveis to administer a dose of from 0.1 to 10 mg per eye per day to thepatient, with treatment continuing so long as the condition persists.

Thus, in an ophthalmic solution, insert, ointment or suspension fortopical delivery, or a tablet, intramuscular, or intravenous compositionfor systemic delivery, the active medicament or an equivalent amount ofa salt thereof is employed, the remainder being carrier, excipients,preservatives and the like as are customarily used in such compositions.

The active drugs of this invention are most suitably administered in theform of ophthalmic pharmaceutical compositions adapted for topicaladministration to the eye such as a suspension, ointment, or as a solidinsert. Formulations of these compounds may contain from 0.01 to 15% andespecially 0.5% to 2% of medicament. Higher dosages as, for example,about 10%, or lower dosages can be employed provided the dose iseffective in reducing or controlling elevated intraocular pressure. As aunit dosage from between 0.001 to 10.0 mg, preferably 0.005 to 2.0 mg,and especially 0.1 to 1.0 mg of the compound is generally applied to thehuman eye, generally on a daily basis in single or divided doses so longas the condition being treated exists.

As with all medications, dosage requirements are variable and must beindividualized on the basis of the disease and the response of thepatient.

The pharmaceutical preparation which contains the active compound may beconveniently admixed with a non-toxic pharmaceutical organic carrier, orwith a non-toxic pharmaceutical inorganic carrier. Typical ofpharmaceutically acceptable carriers are, for example, water, mixturesof water and water-miscible solvents such as lower alkanols oraralkanols, vegetable oils, polyalkylene glycols, petroleum based jelly,ethyl cellulose, ethyl oleate, carboxymethylcellulose,polyvinylpyrrolidone, isopropyl myristate and other conventionallyemployed acceptable carriers. The pharmaceutical preparation may alsocontain non-toxic auxiliary substances such as emulsifying, preserving,wetting agents, bodying agents and the like, as for example,polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500,4,000, 6,000 and 10,000, antibacterial components such as quaternaryammonium compounds, phenylmercuric salts known to have cold sterilizingproperties and which are non-injurious in use, thimerosal, methyl andpropyl paraben, benzyl alcohol, phenyl ethanol, buffering ingredientssuch as sodium chloride, sodium borate, sodium acetates, gluconatebuffers, and other conventional ingredients such as sorbitanmonolaurate, triethanolamine, oleate, polyoxyethylene sorbitanmonopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol,thiosorbitol, ethylenediamine tetraacetic acid, and the like.Additionally, suitable ophthalmic vehicles can be used as carrier mediafor the present purpose including conventional phosphate buffer vehiclesystems, isotonic boric acid vehicles, isotonic sodium chloridevehicles, isotonic sodium borate vehicles and the like.

The pharmaceutical preparation may also be in the form of a solid insertsuch as one which after dispensing the drug remains essentially intact,or a bio-erodible insert that either is soluble in lacrimal fluids, orotherwise disintegrates.

The following examples of ophthalmic formulations are given by way ofillustration.

EXAMPLE 1

    ______________________________________                                        A compound of Formula (I)                                                                         1     mg.      15  mg.                                    Monobasic sodium phosphate.2H.sub.2 O                                                             10    mg.      5   mg.                                    Dibasic sodium phosphate.12H.sub.2 O                                                              30    mg.      15  mg.                                    Benzalkonium chloride                                                                             0.1   mg.      0.1 mg.                                    Water for injection q.s. ad.                                                                      1.0   ml.      1.0 ml.                                    ______________________________________                                    

Compound A, phosphate buffer salts, and benzalkonium chloride are addedto and dissolved in water. The pH of the composition is adjusted to 6.8and diluted to volume. The composition is rendered sterile by ionizingradiation.

EXAMPLE 2

    ______________________________________                                        A Compound of formula (I)                                                                              5 mg.                                                petrolatum q.s. ad.      1 gram                                               ______________________________________                                    

The active compound and the petrolatum are aseptically combined.

EXAMPLE 3

    ______________________________________                                        A Compound of formula (I)                                                                          1 mg.                                                    Hydroxypropylcellulose q.s.                                                                       12 mg.                                                    ______________________________________                                    

Ophthalmic inserts are manufactured from compression molded films whichhare prepared on a Carver Press by subjecting the powdered mixture of theabove ingredients to a compressional force of 12,000 lbs. (gauge) at300° F. for one to four minutes. The film is cooled under pressure byhaving cold water circulate in the platen. Ophthalmic inserts are thenindividually cut from the film with a rod-shaped punch. Each insert isplaced into a vial, which is then placed in a humidity cabinet (88% R.H.at 30° C.) for two to four days. After removal from the humiditycabinet, the vials are stoppered and then capped. The vials containingthe hydrate insert are then autoclaved at 250° F. for 1/2 hour.

EXAMPLE 4

    ______________________________________                                        A Compound of formula (I)                                                                            1 mg.                                                  Hydroxypropyl cellulose q.s. ad.                                                                    12 mg.                                                  ______________________________________                                    

Ophthalmic inserts are manufactured from a solvent cast film prepared bymaking a viscous solution of the powdered ingredients listed above usingmethanol as the solvent. The solution is placed on a Teflon plate andallowed to dry at ambient conditions. After drying, the film is placedin an 88% R. H. cabinet until it is pliable. Appropriately sized insertsare cut from the film.

EXAMPLE 5

    ______________________________________                                        A Compound of formula (I)                                                                              1 mg.                                                Hydroxypropylmethyl cellulose q.s. ad.                                                                12 mg.                                                ______________________________________                                    

Ophthalmic inserts are manufactured from a solvent cast film which isprepared by making a viscous solution of the powdered blend of the aboveingredients using a methanol/water solvent system (10 ml. methanol isadded to 2.5 g. of the powdered blend, to which 11 ml. of water (inthree divided portions) is added. The solution is placed on a Teflonplate and allowed to dry at ambient conditions. After drying, the filmis placed in an 88% R. H. cabinet until it is pliable. Appropriatelysized inserts are then cut from the film.

EXAMPLE 6

    ______________________________________                                        A Compound of formula (I)                                                                              1 mg.                                                Hydroxypropylmethyl cellulose q.s. ad.                                                                12 mg.                                                ______________________________________                                    

Ophthalmic inserts are manufactured from compression molded films whichare prepared on a Carver Press by subjecting the powdered mixture of theabove ingredients to a compressional force of 12,000 lbs. (gauge) at350° F. for one minute. The film is cooled under pressure by having coldwater circulate in the platen. Ophthalmic inserts are then individuallycut from the film with a punch. Each insert is placed into a vial, whichis then placed in a humidity cabinet (88% R. H. at 30° C.) for two tofour days. After removal from the humidity cabinet, the vials arestoppered and then capped. The vials containing the hydrated insert arethen autoclaved at 250° F. for one-half hour.

It is highly preferred that the solid inserts of this invention areavailable for use by the patient in a pathogen free condition. Thus, itis preferred to sterilize the inserts and to insure againstrecontamination, the sterilization is preferably conducted afterpackaging. The best mode of sterilizing is to employ ionizing radiationincluding radiation emanating from Cobalt 60 or high energy electronbeams.

EXAMPLE 7

The following materials are admixed in a 1250 ml bottle: 24 g of anactive compound of formula (I) which is a sufficient amount ofmedicament to result in a concentration of 10 mg per ml in the finalsamples, allowing for previously established 3.0% average; 0.4 g sodiumbisulfite, 12 g NaCl, and 28 ml water (at 180° F.). This mixture, (I),is autoclaved for 30 minutes at 121° C. under 15 psig. Separately, 3 gof hydroxyethylcellulose in 720 ml of water (II) and 0.4 g of lecithinin 80 ml of water (III) were autoclaved for 30 minutes at 121° C. Then,(III) is admixed with (I) for 2 hours, and the resultant mixture pouredinto (II). Another mixture (IV) is prepared from 20 g of sorbitol, 2.36ml of benzalkonium chloride, 10 g of disodium edetate, and water to givea final solution volume of 900 ml. Then, (IV) is added to the mixture of(I), (II), and (III) in sufficient quantity to give 1.8 l. overall. The1.8 l. mixture of I, II, III, and IV is then taken and homogenized usinga homogenizer at 2000 psig. Stock solutions are then prepared forpolyoxyethylene (20) sorbitan monooleate by dissolving 3 g of thematerial in 100 ml of water, and of benzyl alcohol/β-phenyl-ethylalcohol by admixing 50 ml of each alcohol. Varying quantities of the twostock solutions are then added to four 90 ml aliquots of the homogenizedmixture of (I), (II), (III), and (IV) prepared as described above,together with sufficient water to give a total of 100 ml for each offour different samples.

Other formulations, in an oil vehicle and an ointment are exemplified inthe following examples.

EXAMPLE 8

Solution Composition

    ______________________________________                                        A compound of formula (I)                                                                          0.1 mg.                                                  Peanut oil q.s. ad. 0.10 mg.                                                  ______________________________________                                    

The solution is rendered sterile by filtration through a sterilizingfilter.

EXAMPLE 9

    ______________________________________                                        A compound of formula (I)                                                                             0.5   gm.                                             Petrolatum q.s. ad.     1     gram                                            ______________________________________                                    

The compound and the petrolatum are aseptically combined.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

The following examples illustrate the preferred procedures for thesynthesis of the compounds of the present invention.

EXAMPLE 10N-(2,2-Diphenylethenyl)-2-hydroxybenzo(b)thiophene-3-carboxamide

A stirred mixture of 2-hydroxybenzo(b)thiophene-3-carboxamide (0.485 g,0.0025 m), diphenylacetaldehyde (0.51 g, 0.0026 m), p. toluenesulfonicacid hydrate (30 mg), and dried toluene (15 ml) is set in an oil-bath at100° C., the bath temperature raised to 150° C., and the mixture heatedunder reflux until thin-layer chromatography of the mixture indicatescompleteness of reaction. The cooled reaction mixture is concentrated invacuo and the residue chromatographed on silica gel (v/v 10-50% CH₂ Cl₂in hexane) to yieldN-(2,2-Diphenylethenyl)-2-hydroxybenzo(b)thiophene-3-carboxamide.

EXAMPLE 11 2-Hydroxybenzo(b)thiophene-3-carboxamide

Method A:

Under a nitrogen atmosphere, a mixture of o-mercaptophenylmalonamic acid(2.1 g, 0.01 m), dimethylformamide (20 ml), and concentratedhydrochloric acid (0.2 ml) are heated in an oil-bath at ca. 100° C.until thin-layer chromatography indicates the absence of startingmalonamic acid. The cooled, stirred mixture is diluted with ice-water,aged and filtered to yield 2-hydroxybenzo(b)thiophene-3-carboxamide.

Method B:

Methyl o-mercaptophenylmalonamate (4.5 g, 0.02 m) and drieddimethylformamide (50 ml) at 10° C. is treated with sodium methoxide(3.2 g, 0.06 m) under a nitrogen atmosphere, and the resultant mixtureallowed to stir at ambient temperature until no starting malonamateremains (thin-layer analysis). The reaction mixture is added to astirred excess dilute hydrochloric acid-ice mixture, aged and filteredto yield 2-hydroxybenzo(b)thiophene-3-carboxamide.

When the starting malonamic derivatives of steps A and B are replacedwith the corresponding N-benzyl analogs,N-benzyl-2-hydroxybenzo(b)thiophene-3-carboxamide is obtained.

Method C:

A mixture of N-benzyl-2-hydroxybenzo(b)thiophene-3-carboxamide (4.3 g,0.016 m), 10% palladium on carbon (2.0 g), and ethanol are stirred undera hydrogen atmosphere (40 p.s.i.) at 35° C. until hydrogen uptake iscompleted. The reaction mixture is filtered, the cake washed well withwarm ethanol, and the combined filtrates concentrated in vacuo to yield2-hydroxybenzo(b)thiophene-3-carboxamide.

Method D:

To a stirred mixture of benzthiophene-2-one (1.50 g, 0.01 m),phenylcarbamate (1.4 g, 0.01 m), and hexamethylphosphorictriamide (2.2ml) at 5° C. is added sodium hydride (0.24 g, from 0.4 g 60% mineral oildispersion), and the resultant mixture stirred at ambient temperaturesfor 5 hours. The volatiles are removed under high vacuum, and theresidue triturated well with hexane and then with water to yield2-hydroxybenzo(b)thiophene-3-carboxamide.

When phenylcarbamate is replaced in the above reaction withN-benzylphenylcarbamate,N-Benzyl-2-hydroxybenzo(b)thiophene-3-carboxamide is obtained.

Method E:

A mixture of 2-acetamido-3-cyanobenzo(b)thiophene (2.2 g, 0.01 m),ethanol (25 ml), water (15 ml) and concentrated hydrochloric acid (25ml) is heated under reflux for 12 hours. The reaction mixture is dilutedwith water, aged and filtered to yield2-hydroxybenzo(b)thiophene-3-carboxamide.

What is claimed is:
 1. A compound of formula: ##STR18## or apharmaceutically acceptable salt thereof wherein R is(a) H; (b) C₁₋₆alkyl; (c) halo C₁₋₆ alkyl; X₂, X₃ independently are(a) H; (b) C₁₋₆alkyl; (c) halo C₁₋₆ alkyl; (d) halo; (e) cyano; (f) methylthio; (g)methylsulfonyl; or (h) formyl; R² and R³ independently are(a) phenyl; or(b) thienyl.
 2. A pharmaceutical composition for treating inflammation,fever and pain in mammalian species comprising a pharmaceuticallyacceptable carrier and an effective amount of a compound of formula:##STR19## or a pharmaceutically acceptable salt thereof wherein R is(a)H; (b) C₁₋₆ alkyl; (c) halo C₁₋₆ alkyl; X₂, X₃ independently are(a) H;(b) C₁₋₆ alkyl; (c) halo C₁₋₆ alkyl; (d) halo; (e) cyano; (f)methylthio; (g) methylsulfonyl; or (h) formyl; R² and R³ independentlyare(a) phenyl; or (b) thienyl.
 3. The compound of claim 1 which isN-(2,2-diphenylethenyl)-2-hydroxybenzo[b]thiophene-3-carboxamide.
 4. Thecompound of claim 1 which isN-(2,2-diphenylethenyl)-2-hydroxy-5-(trifluoromethyl)benzo[b]thiophene-3-carbaxamide.5. The composition of claim 2 which isN-(2,2-diphenylethenyl)-2-hydroxybenzo[b]thiophene-3-carbaxamide.
 6. Thecomposition of claim 2 which isN-(2,2-diphenylethenyl)-2-hydroxy-5-(trifluoromethyl)benzo[b]thiophene-3-carbaxamide.